N-(c mercapto-pyrimidyl)-p-aminobenzenesulfonamides



Patented Sept. 15, 1953 'N- C MERGAP'110-PYRIM'lDYL)--P-AMIN BENZENESULFONAMIDES William A. Lott, Maplewood, and Frank B'er- 'geim, Highland Park, N. J iassignors to Mathieson Chemical Corporation,

corporation of Virginia NoDrawing. Application 'June 21, 1951, Serial No. 2323882 Claims.

This invention relates to, and has for its object the provision of: (A), N-(C-mercapto-pyrimidyl) -p-aminobenzene-sulfonamides; (B), N- (C-mercapto-pyrimidyl) p nitrobenzene-sulfonamides; (C), S-(heavy metal) derivatives of (A); (D) salts of (A) with bases; (E) salts of (C) with bases; and (F) methods of producing (A), (B), (C), (D), (E). These compounds are promising therapeutic agents, the S-(heavy metal) derivatives (C) and salts (E) being preferred because of their combination of chemotherapeutic action of the sulionamides with the therapeutic action of the heavy metals.

Among the (A) and (B) compounds, those having the general formula N R wherein Y is a member of the class consisting of nitro, amino, and acetamido groups, at least one R represents -SH and each remaining R is a member of the class consisting of hydrogen and lower alkyl groups, are also preferred.

A representative compound having the combined chemotherapeutic action referred to hereinbefore, has the following structural formula:

The compounds of this invention may be conveniently prepared by the method which essentially comprises reacting a compound of the general formula:

with an alkali-metal hydrosulfide in va substantially-dry organic solvent for the reactants, wherein one X in the general formula is a member of the class consisting of p-nitrobenzenesulfonamido and p-acetamidobenzenesulfonamido least one X is a halo group, and each remaining X is a member of the class consisting of hydrogen and lower alkyl groups, and recovering the resulting mercapto-pyrimidyl compound. Preferably, the reaction takes place at no higher than 100 C. The amino compounds of this invention are obtained from the corresponding nitro compounds by reduction.

Compounds (C) are prepared by reacting the compound (A) insolution with an inorganic salt of a heavy-metalin a solvent for the reactants. Compounds (D) and (E) are prepared by reacting compound (A) and (C) respectively with New York, N. Y., a

invention Preparation of N-(6=mercapto4-methyZ-2-pyrimidyl) -p-nitrobenzenesulfonamide To 10 g. of N-(6 chloro-4-methyl-2-pyrimidyl) -p-nitrobenzenesu1fonamide .[J. Chem. Soc. 689-92 (1945) 1, in 20 parts, by "weight, of boiling absolute alcohol, is added 7.3 'g. sodium sulfhydrate in 63 ml. absolute alcohol EXAMPLE 2 Preparation of N -(6-mercapto-4-meth1jZ 2-pyl rimidyl) -p-amino-benaenesulfonamide 20 g, of N (6 mercapto-4-methyl-2-pyrimidyl) p nitrobenzenesulfonamide is dissolved in 10 parts, by weight, of concentrated aqueous "ammonia, and hydrogen sulfide is then passed into the solution for about two hours while maintaining a temperature of about 10-25" C. This clear solution is then heated for about one-half hour at'about .100" C. (to dri'veoff Jth'ebulk 'of themused hydrogen sulfide and ammonia), cooled to R; 'I'., treated with 123 m1. normal NaOH and filtered (to remove "the sulfur'by-producti. The

acetic acid to When recrystallized from a mixture of alcohol monohydrate of 'N-(6-mercapto- 4-rnethyl-2epyrimidyl) vp-aminobenzenesulfondrate is confirmed by an analysis of its carbon, hydrogen, and sulfur content.)

EXAMPLE 3 Preparation of an S-bismath derivative of N- (6 mercapto-4-methy-Z-2-pyrimidyl) -p-aminobenzenesalfonamide To 100 cc. of a 0.1 molar solution of N-(G- mercapto-4-methyl-2-pyrimidyl) p aminobenzenesulfonamide, prepared as in Example 2 in absolute alcohol, is added 33 cc. of a 0.1 molar solution of bismuth trichloride in propylene glycol. The yellow precipitate which forms is filtered off, washed with water and dried. The product is believed to have the formula C HaC-- a EXALEPLE 4 Preparation of the disodiam salt of an S-mercury bis derivative of N (6 mercapto-4- methyl 2 pyrimidyl) -p-aminobenzenesalfonamide To 5 g. of the monohydrate of N-(G-mercapto- 4-methyl-2-pyrimidyl) p aminobenzenesulfonamide, prepared as given in Example 2, in 159 ml. normal sodium hydroxide, is added dropwise, over a one-half hour period, a solution of 2.1 g. of mercuric chloride in 64 ml. 50% alcohol; and the yellowish-white precipitate of the mercury salt which forms is filtered off and washed free of chloride ion. This precipitate is then treated with sufficient dilute sodium hydroxide to dissolve almost all the solid, is filtered, the filtrate is concentrated to dryness in vacuo, and the product, a faintly yellow, fluiiy powder, is obtained. The composition corresponds with that of the disodium salt of the mercury-bis derivative of N-(6-mercapto-4-methyl-2-pyrimidyl)- paminobenzenesulfonamide, and contains varying amounts of water (dependent upon the method of drying). Thus, a product dried in vacuo at room temperature for 24 hours had a composition corresponding with the tetrahydrate.

EXAMPLE 5 Preparation of the sodium salt of the S-silver derivative of N (6 mercapto 4 methyl-2- pyrimidyl) -p-amiriobenzenesalfonamide 157 mg. of the monohydrate of N-(fi-mercapto- 4-methyl-2-pyrimidyl) p aminobenzenesulfonamide is dissolved in 5 ml. normal sodium hydroxide, filtered to remove a small amount of insoluble material, and to the filtrate is added 81 mg. silver nitrate in 1 ml. water. A yellow precipitate of silver salt, which forms immediately, is filtered ofi, washed with water until free from nitrate ion and then treated with sufficient normal sodium hydroxide to dissolve it. When this solution is concentrated to dryness in high vacuo, a pale yellow, rlufiy powder is obtained.

Manifestly a number and variety of other N- (C-mercaptopyrimidyl) p nitrobenzenesulfonamides (or corresponding acetamidobenzenesulfonamides) may be obtained by the procedure given in Example 1, using the appropriate alkalimetal hydrosulfide (including ammonium hydrosulfide) and the N-(C-halo-pyrimidyl)-p-nitrobenzenesulfonamide (or the corresponding pacetamidobenzenesulfonamide) reactants (I). The following additional reactants (I), inter alia.

may be used for the preparation of the compounds of this invention:

N (5 bromo 4 methyl-2-pyrimidyl) -p-nitrobenzenesulfonamide, [J. A. C. S. 63: 3028 (41)] N (5-bromo-4,6-dimethyl-2-pyrimidyl) -p-nitr0- benzenesulfonamide, [J Org. Chem. 10: 327 (45)] N- (5-chloro-2-pyrimidyl) -p-nitrobenzenesu1fonamide, [J. A. C. S. 64: 567 (42)] N- (2-ch1oro-5-pyrimidy1) -pnitrobenzenesulfonamide, [J. A. C. S. 64: 567 (42)] N (2 ,4-dichloro -5 -pyrimidyl) -p -nitrobenzenesulfonamide [prepared from N(2,4-dihydroxy-5- pyrimidyl) p nitrobenzenesulfonamide (Brit. Pat. 555,865) by interaction with P0013] Manifestly, a number and variety of other S- (heavy-metal) derivatives of [A] and salts of the derivatives may be obtained by the procedure given in Examples 3, 4, and 5, thus:

The gold derivative is prepared from bromauric acid and N-(fi-methyli-mercapto-2-pyrimidyl) p-aminobenzenesulfonamide (referred to hereinafter as II);

The copper derivative is prepared from cupric chloride and II;

- The cobalt derivative is prepared from cobaltous chloride and II;

The nickel derivative is prepared from nickel chloride and II;

The iron derivative is prepared from chloride and II;

The arsenic derivative arsenous chloride and II;

The antimony derivative is prepared antimony trichloride and II;

The cadmium derivative is mium trichloride and II.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. compound of the general formula:

N=(IJS- i nrwOsomv-d o-rw] M i t t-R wherein X is a member of the class consisting of hydrogen and alkali-metal, M is a heavy metal of the class consisting of mercury, silver, gold, copper, cobalt, nickel, iron, arsenic, antimony, cadmium and bismuth, B. and R are each members of the class consisting of hydrogen and lower alkyl, and 7b is the valence of the metal lVl.

2. A compound as defined by claim 1, in which M is mercury.

3. A compound as defined by claim M is silver.

4. The disodium salt of the S-mercury-bis-deriv-ative of N-(6-mercapto-4-methyl-2-pyrimidyl) -paminobenzenesulfonamide.

The sodium salt of the S-silver derivative of N (6 mercapto 4 methyl-2-pyrimidyD-paminobenzenesulfonamide.

WILLIAM A. LOTT. FRANK I-I. BERG-131M.

ferric is prepared from from prepared from cad- 1, in which References Gited in the file of this patent UNITED STATES PATENTS Number Name Date 2,410,793 Winnek et al Nov. 5, 1940 2,430,439 Winnek et a1 Nov. 4, 1947 FOREIGN PATENTS Number Country Date 589,040 Great Britain June 10, 1947 

1. A COMPOUND OF THE GENERAL FORMULA: WHEREIN X IS A MEMBER OF THE CLASS CONSISTING OF HYDROGEN AND ALKALI-METAL, M IS A HEAVY METAL OF THE CLASS CONSISTING OF MERCURY, SILVER, GOLD, COPPER, COBALT, NICKEL, IRON, ARSENIC, ANTIMONY, CADMIUM AND BISMUTH, R" AND R''" ARE EACH MEMBERS OF THE CLASS CONSISTING OF HYDROGEN AND LOWER ALKYL, AND N IS THE VALENCE OF THE METAL M. 